Synthesis and Pharmacological Evaluation of 5‑Pyrrolidinylquinoxalines as a Novel Class of Peripherally Restricted κ‑Opioid Receptor Agonists

5-Pyrrolidinyl substituted perhydroquinoxalines were designed as conformationally restricted κ-opioid receptor agonists restricted to the periphery. The additional N atom of the quinoxaline system located outside the ethylenediamine κ pharmacophore allows the fine-tuning of the pharmacodynamic and pharmacokinetic properties. The perhydroquinoxalines were synthesized stereoselectively using the concept of late stage diversification of the central building blocks <b>14</b>. In addition to high κ-opioid receptor affinity they demonstrate high selectivity over μ, δ, σ₁, σ₂, and NMDA receptors. In the [³⁵S]­GTPγS assay full agonism was observed. Because of their high polarity, the secondary amines <b>14a</b> (log <i>D</i>_7.4 = 0.26) and <b>14b</b> (log <i>D</i>_7.4 = 0.21) did not penetrate an artificial blood–brain barrier. <b>14b</b> was able to inhibit the spontaneous pain reaction after rectal mustard oil application to mice (ED₅₀ = 2.35 mg/kg). This analgesic effect is attributed to activation of peripherally located κ receptors, since <b>14b</b> did not affect centrally mediated referred allodynia and hyperalgesia